The delivery of medicinal formulations (e.g., a drug suspended or dissolved in a carrier) to the lungs by way of inhalation is an important means for treating a variety of conditions, including such common conditions as bronchial asthma and chronic obstructive pulmonary disease. Steroids, β-2 agonists, and anti-cholinergic agents are among the drugs that are administered to the lung for such purposes. Such drugs are commonly administered in an aerosol form. To assure that the particles are of a respirable size (e.g., from about 5 to 10 microns in diameter), the particles can first be prepared in an appropriate size and subsequently incorporated into a suspension suitable for use with a propellant to thereby provide an aerosol formulation. Alternatively, formulations can be prepared in solution form in order to avoid the concern for proper particle size in the formulation. Solution formulations must nevertheless be dispensed in a manner that produces particles or droplets of respirable size. Once prepared, aerosol formulations are contained within an appropriate aerosol canister equipped with a metered dose valve. In the hands of a patient, the formulation may then be dispensed via a metered dose inhaler (“MDI”) by activating an actuator that directs a predetermined dosage of medication from the valve to the patient.
Aerosol formulations are desirably dispensed from their containers or canisters in a reproducible predetermined dosage. The reproducibility of the dosage can be problematic due to any of a variety of events that may occur in suspension formulations including, for example, rapid creaming, settling, or flocculation. Mechanical problems may also occur to create problems relating to dosage reproducibility. Typical mechanical problems involve valve failure, which can range from the total inoperability of the valve to the partial or sporadic operability accompanying the attempted use of a “sticky” valve. In order to overcome the problems associated with aerosol formulations, such formulations often include surfactants to aid in stabilizing a suspension and thereby facilitate more reproducible dosing. Additionally, some surfactants can also function as lubricants to control and potentially eliminate mechanical problems by providing a measure of lubrication to aid in the smooth actuation of a metered dose valve. Any of a variety of materials may be used as dispersing aids in aerosol formulations. But, the desirability of any particular material is often dependent on the identity of the particular drug and propellant (or class of propellants) being used in a particular medicinal formulation.
One of the recognized difficulties in the formulation of medicinal suspensions and the like has been the difficulty in dissolving sufficient quantities of surfactants in various hydrofluoroalkane (HFA) propellants such as HFA-134a and HFA-227. Cosolvents have been added to medicinal formulations as one approach to addressing and overcoming this problem. Another approach avoids the use of cosolvents and provides sufficient amounts of surfactants in a medicinal formulation by the use of specific materials that are soluble in HFA propellants and are effective surfactants or dispersing aids in an aerosol formulation. Among such materials are certain fluorinated surfactants and certain polyethoxy surfactants.
Materials used in medicinal aerosol formulations that are delivered into the lungs are preferably non-toxic (e.g., “biocompatible”) and are readily metabolized or eliminated from the body over time (e.g., “biodegradable”). Biocompatible and biodegradable polymers generally comprise a class of materials useful in the delivery of drugs to the lungs as well as to other areas of the body. For example, polymeric esters of selected hydroxycarboxylic acids or their derivatives (e.g., lactic acid, glycolic acid, p-dioxanone, etc.) are both biocompatible and biodegradable in the human body. These polymeric esters degrade over time into their constituent hydroxycarboxylic acids that can then be metabolized and naturally eliminated from the body. Biocompatible polymers have been used as solubilizing and/or stabilizing aids as well as vehicles for the delivery and sustained or controlled release of drugs. Such biocompatible polymers have been used in the formulations of certain drugs dispensed by MDIs into the lungs. While their use has been beneficial, the manufacture of biocompatible polymers has not been problem free. For example, certain acylated polymeric hydroxycarboxylic acids have proven to be useful in formulations dispensed through MDIs. But, the process for manufacturing such acylated polyhydroxycarboxylic acids also generates side products that can destabilize the polymer.
The manufacture of acylated polymeric hydroxycarboxylic acids is accomplished via a reaction between a polyhydroxycarboxylic acid and a suitable anhydride. However, the reaction also generates a mixed anhydride (e.g., anhydride formed between the terminal acid of a polymeric hydroxycarboxylic acid and another carboxylic acid group). In the past, the mixed anhydride has been hydrolyzed with added water. But, the hydrolysis reaction can be difficult to control and has been known cause hydrolysis of ester bonds along the length of the polymer chain resulting in the generation of additional non-acylated polyhydroxyacid comprising its own acid hydroxyl groups which tends to destabilize the biopolymer. The presence of these reactive hydroxyl groups can lead to further undesired side products.
It is desirable to provide medicinal compositions such as those comprising stable biocompatible polymer formulations. It is also desirable to provide methods for the manufacture of such medicinal compositions wherein the method for the manufacture of the medicinal compositions further minimize the potential for the creation of undesired reaction products.